PCT WO/02/46171 describes a series of anilinopyrimidine derivatives and among them the anilinopyrimidine derivative having the formula: 1-(4{4-[4-(4-Chloro-phenyl)-pyrimidin-2-ylamino]-benzoyl}-piperazin-1-yl)-ethanone (see Formula (I) above).
Frelin and al. (Blood, 15 Jan. 2005 Volume 105, Number 2, pages 804-811) have show that AS602868, an anilinopyrimidine derivative corresponding to the compound of Formula I above and covered by the patent application No PCT WO/02/46171, induces cell death in most primary fresh cells from Acute Myeloid Leukemia (AML) patients. These results strongly suggest that pharmacologic inhibition of the NF-kB pathways could be an interesting adjuvant approach in future treatments for AML.
Acute Myeloid Leukemia (AML) is characterized by invasion of the bone marrow by leukemic myeloid blasts arrested at various maturation steps. Despite advances in diagnosis of the different subtypes of AML and progress in therapeutic approaches, current chemotherapies produce only initial remission. Relapse often occurs, and AML is finally fatal in more than 70% of cases. Dysregulation of malignant hematopoietic stem/progenitor cells (leukemic stem cells, LSCs) produces blast cells with differentiation defects. LSCs, which are quiescent or slowly cycling and therefore less sensitive to chemotherapy, are responsible for disease relapse and represent the target for future innovative therapies.
LSCs are both phenotipically and biologically similar to normal hematopoietic stem cells (HSCs), making discrimination and targeting difficult. One interesting difference is a constitutive activation of the nuclear factor-kB (NF-kB) transcription factor in LSC and AML blasts but not in HSCs. Such subnormal constitutive NF-kB activation has been detected in two other hematopoietic cancers, Hodgkin lymphoma and acute lymphoid leukemia, as well as in various solid tumors. Transcription factors of the NF-kB family are regulators of cell proliferation and survival and control expression of several genes relevant to the tumorigenic process.
For instance, NF-kB promotes cell survival through expression of gene coding for antiapoptotic proteins (cellular inhibitor of apoptosis protein-1, (c-IAP1), c-IAP2, bfl-1 and bcl-x1). NF-kB is also known to stimulate cell proliferation via induction of growth factors (interleukin-2 (IL-2), granulocyte-macrophage colony stimulating factor (GM-CSF)) or cell cycle regulators (cyclin D1 and c-myc). NF-kB could participate in the resistance of tumor cells to treatments after expression of the multidrug resistance (MDR) protein. NF-kB could promote metastasis through induction of the extracellular matrix-degrading enzymes matrix metalloproteinase 9 (MMP9) and urokinase-type plasminogen activator (uPA). In addition, most actual antineoplastic drugs also activate NF-kB, an event that interferes with the treatments.
It has therefore been proposed that inhibition of NF-kB could be an adjuvant therapy for cancer. NF-kB dimers are maintained inactive in the cytosol by inhibitory subunits of the IkB family. Upon cell triggering by a wide spectrum of stimuli, IkB molecules are phosphorilated on 2 critical serine residues by 2 highly related specific kinases, IKK1, or α, and IKK2, or β, which together with the scaffold protein IKKγ/NF-kB essential modulator (NEMO) form the IKK complex that integrates signals for NF-kB activation. Serine phosphorylation results in polyubiquitination of IkB and its subsequent degradation by proteasome. If transfection of a superrepressor form of the IkB-α inhibitory molecule is highly specific to block NF-kB, its use is restrained to cell lines.
It was shown that pharmacological blockade of the IKK2 kinase with an anilinopyrimidine derivative covered by the patent application PCT WO/02/46171 prevented TNF-α induced NF-kB activation in Jurkat leukaemic cells (Frelin and al. Oncogene 2003 (22) pages 8187-8194) and therefore that these derivatives can be used as adjuvant in the treatment of cancer, preferably wherein the cancer is of the colon, AML, rectum, prostate, liver, lung, bronchus, pancreas, brain, head, neck, stomach, skin, kidney, cervix, blood, larynx, esophagus, mouth, pharynx, testes, urinary bladder, ovary or uterus.